Mutations in the Human Gonadotropin-Releasing Hormone Receptor: Insights into Receptor Biology and Function
Abstract
Pulsatile hypothalamic release of GnRH tightly controls reproduction by activating a specific cell membrane receptor (GnRHR) on the surface of pituitary gonadotrophs to stimulate luteinizing hormone and follicle-stimulating hormone secretion. During the last 10 years, 21 loss-of-function GNRHR mutations have been identified in patients with idiopathic hypogonadotropic hypogonadism. Although most patients with hypogonadotropic hypogonadism can be treated by delivery of exogenous pulsatile GnRH, in several cases, patients with GNRHR mutations fail to respond efficiently to GnRH treatment. The impact of each mutation on GnRHR function has been studied extensively in vitro, but correlation with clinical phenotype is not always evident. By combining recent advances into the molecular mechanisms controlling ligand binding and receptor activation with data accumulated from clinical studies, this review summarizes the overall structure-function relationships of the human GnRH receptor, with an emphasis on the impact of naturally occurring mutations. Furthermore, given that it was recently demonstrated that pharmacological chaperones can rescue altered receptor function in vitro, potential therapeutic approaches are also discussed.
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During the past 10 years, at least 19 additional loss-of-function mutations in the GnRH receptor have been identified in patients with IHH.
“During the past 10 years, at least 19 additional loss-of-function mutations in the GnRH receptor have been identified in patients with IHH.72”
From The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism (2009) · cites this paper as [72]
Large-scale screening indicates that GNRHR mutations account for 3.5-16% of sporadic cases of normosmic IHH and up to 40% of familial cases of normosmic IHH.
“Large-scale screening indicates that GNRHR mutations account for 3.5–16% of sporadic cases of normosmic IHH and up to 40% of familial cases of normosmic IHH (Table 1).72”
From The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism (2009) · cites this paper as [72]
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- Authors
- Bédécarrats, G., & Kaiser, U.
- Affiliations
- University of Guelph (CA)
- Brigham and Women's Hospital (US)
- Venue
- Seminars in Reproductive Medicine
- Publisher
- Georg Thieme Verlag KG
- Published
- 2007-09
- Volume
- 25
- Issue
- 5
- Pages
- 368-378
- ISSN
- 1526-4564 (ISSN-L)
- 1526-8004
- OpenAlex
- W1966197692
- Cited by
- 63
- References
- 0
- Citations by year
- 2026: 1 · 2025: 1 · 2023: 4 · 2022: 2 · 2021: 3 · 2019: 3 · 2017: 5 · 2016: 3 · 2015: 1 · 2014: 3 · 2013: 4 · 2012: 7
- FWCI
- 7.37
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Seminars in Reproductive Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01 HD19938, R01HD019938, U54HD28138, U54HD028138)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
- Keywords
- GnRH receptor, idiopathic hypogonadotropic hypogonadism, loss-of-function mutations, pulsatile GnRH therapy, ligand binding, receptor activation, structure-function relationship, pharmacological chaperones, gonadotrophs
- MeSH terms
- Amino Acid Sequence, Binding Sites, Gene Expression Regulation, Genotype, Humans, Hypogonadism, Gonadotropin-Releasing Hormone, Ligands, Molecular Sequence Data, Mutation, Phenotype, Protein Conformation, Receptors, LHRH, Reproduction, Structure-Activity Relationship, Signal Transduction, Protein Folding, Molecular Chaperones, Hormone Replacement Therapy
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